Advanced therapies are expected to play a crucial role in supporting repair after injury, halting the degeneration of musculoskeletal tissue to enable and promote physical activity. Despite advancements, the progress in developing advanced therapies in orthopaedics lags behind specialties like oncology, since innovative regenerative treatment strategies fall short of their expectations in musculoskeletal clinical trials. Researchers should focus on understanding the mechanism of action behind the investigated target before conducting clinical trials. Strategic research networks are needed that not only enhance scientific exchange among like-minded researchers but need to include early on commercial views, companies and venture perspectives, regulatory insights and reimbursement perspectives. Only in such collaborations essential roadblocks towards clinical trials and go-to-patients be overcome.

Hyaluronic acid (HA), a naturally occurring polysaccharide, holds immense potential in regenerative medicine due to its diverse biological functions and clinical applications, particularly in gel formulations. This paper presents a comprehensive exploration of HA, encompassing its origins, molecular characteristics, and therapeutic roles in gel-based interventions. Initially identified in bovine vitreous humor, HA has since been found in various tissues and fluids across vertebrate organisms and bacterial sources, exhibiting consistent physicochemical properties. The synthesis of HA by diverse cell types underscores its integral role in the extracellular matrix and its relevance to tissue homeostasis and repair. Clinical applications of HA, particularly in addressing musculoskeletal ailments such as osteoarthritis, are examined, highlighting its efficacy and safety in promoting tissue regeneration and pain relief. Building upon this foundation, a novel classification system for HA-based interventions is proposed, aiming to standardize treatment protocols and optimize patient outcomes. The ViSCNOVAS classification system refers to viscosity, storage, chain, number, origin, volume, amount, and size. This classification is specifically designed for HA-based orthobiologic products used in regenerative medicine, including orthopedics, sports medicine, aesthetics, cosmetic dermatology, and wound healing. It aims to provide clinicians with a structured framework for personalized treatment strategies. Future directions in HA research are also discussed, emphasizing the need for further validation and refinement of the proposed classification system to advance the field of regenerative medicine. Overall, this manuscript elucidates the biological functions of hyaluronic acid and its potential in clinical practice while advocating for standardization to enhance patient care in various regenerative applications.

Spinal fusion is a prevalent surgical intervention for degenerative spinal diseases, with increasing demand driven by ageing populations. The coexistence of multiple chronic conditions, termed multimorbidity, often complicates surgical outcomes, making advanced bone grafts crucial for successful fusions. This paper reviews the development, clinical application, and controversies surrounding the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgeries. A comprehensive narrative review was conducted, focusing on literature from January 1980 to January 2024, sourced from PubMed and Google Scholar. Studies included those examining rhBMP-2 specifically in spinal fusion contexts, excluding other bone morphogenetic proteins (BMPs) and non-spinal applications. This review presents an overarching synopsis of rhBMP-2, its development history and clinical efficacy, the emergence of side effects, and evolving patterns of clinical use. As discussed in this review, clinical practice has adjusted usage and dosages to mitigate adverse effects, yet the need for safer delivery mechanisms persists. rhBMP-2 remains a potent osteoinductive agent with comparable fusion success, as measured by radiographic fusion and good clinical outcomes, to autologous grafts but poses unique risks. This review sets out how further research is essential to optimise the delivery of rhBMP-2 to reduce side effects. Enhanced understanding and innovation of spatio-temporal presentation relative to endogenous BMP could significantly improve patient outcomes in spinal fusion surgeries. The review contributes to the growing body of literature on the use of rhBMP-2 in spine surgery and discusses changing patterns of clinical use over time.

Osteoarthritis (OA) is a prevalent musculoskeletal disease affecting middle-aged and elderly individuals, with knee pain as a common complaint. Standard therapy approaches generally attempt to alleviate pain and inflammation, using various pharmacological and non-pharmacological options. However, the efficacy of these therapies in long-term tissue repair remains debated. As an alternative, regenerative medicine offers a promising strategy, with decreased adverse event rates and increasing evidence of safety and efficacy. This review will outline current advances in regenerative medicine for knee OA, emphasizing outpatient clinic-based therapies that use orthobiological and non-biological products. Different strategies based on orthobiologics are discussed as potential regenerative options for the management of knee OA. Cell-free therapies including platelet-rich plasma, autologous anti-inflammatories, exosomes, human placenta extract, and mitochondrial transplantation are discussed, focusing on their potential for cartilage regeneration. Additionally, cell-based therapies with regenerative properties including bone marrow aspirate concentrate, adipose stromal vascular fraction, microfat, nanofat, stem cell therapy, and genetically modified cells as part of orthobiologics, are being investigated. Also, this study is looking into non-biological approaches such as using gold-induced cytokines, extracorporeal shockwave therapy, and ozone therapy. The mechanisms of action, effectiveness, and clinical applications of each therapy are being explored, providing insights into their role in the management of knee OA.

Patellar tendinopathy is a relatively common cause of anterior knee pain in athletes. It is predominantly seen in sports involving jumping, running, abrupt change in direction like basketball, volleyball, soccer, sprinting and jumping. The main pathophysiology is considered to be repetitive microtrauma at the inferior pole of patella along with a poor healing response. Although eccentric exercises have shown to be beneficial, the improvement is often slow and may result in a less than satisfactory outcome. There is a growing interest of orthobiologics, mainly platelet-rich plasma (PRP) in multiple chronic musculoskeletal pathologies. This narrative review aimed to analyse the current evidence on the role of orthobiologics in the management of recalcitrant patellar tendinopathy. Multiple studies have shown significant clinical improvement with negligible adverse effects on PRP injection for patellar tendinopathy. Most studies assessed report that the effects of PRP are sustained. However, among all studies evaluated, there is a considerable heterogeneity in terms of PRP composition, number of injections, dosage interval and postinjection rehabilitation protocol, pointing to the need for further research to enable standardisation of PRP therapy. Stem cells too have shown potential to be effective as a treatment modality for chronic patellar tendinopathy, but there is limited data to recommend its use outside of research setting or to enable a meaningful comparison to PRP. There is a promising role of orthobiologics in management of chronic patellar tendinopathy not responding to conventional treatment.
UNASSIGNED: Not applicable (narrative review).

UNASSIGNED: Meniscus tears are a common cause of knee pain encountered in orthopedics and sports medicine. There are numerous management strategies, from physical therapy and oral medications to surgery. Recent evidence is more favorable for conservative management, as operative treatment has limited clinical benefits and is associated with an accelerated progression toward osteoarthritis. Injections with orthobiologic therapies, such as platelet-rich plasma (PRP), are emerging as an alternative therapeutic tool for degenerative tears. This study aims to evaluate the latest evidence regarding the efficacy of PRP injections for the nonoperative management of degenerative meniscal pathology.
UNASSIGNED: Articles were obtained from Embase, PubMed, World of Science, Cochrane, and Galileo databases after searching \"Platelet-rich plasma\" AND \"Meniscus.\" Inclusion criteria consisted of original, human studies evaluating the use of platelet-rich plasma for nonoperative management of meniscus tears.
UNASSIGNED: A total of 384 articles were screened, with ten studies selected for final inclusion. The pooled study population comprised 686 patients, with an average age ranging from 33 to 53 years, and a 38% female population. Three different injection approaches were utilized, categorized as intra-articular alone (IA), intra-meniscal alone (IM), or a combination of both. Most studies demonstrated improved pain and functionality by 3 months that persisted for at least one year. Within the IA and IM groups, the majority of patients were either radiographically stable (30-70%) or demonstrated interval healing (40-60%). Several studies within IM and combined treatment groups evaluated rates and time to arthroscopy, and found lower failure rates and greater arthroscopy-free survival time than control comparison groups.
UNASSIGNED: PRP appears to be a safe and efficacious treatment strategy for degenerative meniscal pathology. However, due to diverse periprocedural techniques, PRP injectate characteristics, and a lack of high-quality studies, additional trials are needed to provide greater a degree of confidence in PRP\'s clinical impact on patients with meniscus tears.
UNASSIGNED: Systematic Review.

UNASSIGNED: Osteoarthritis (OA), a chronic inflammatory joint disorder, still lacks effective therapeutic interventions. Consequently, the development of convenient experimental models is crucial. Recently, research has focused on the plasticity of Mesenchymal Stem/stromal Cells, particularly adipose-derived ones (ASCs), in halting OA progression. This study investigates the therapeutic potential of a cell-free approach, ASC-derived conditioned medium (CM), in reversing cytokine-induced OA markers in an ex vivo model of human cartilage explants.
UNASSIGNED: 4 mm cartilage punches, derived from the femoral heads of patients undergoing total hip replacement, were treated with 10 ng/ml TNFα, 1 ng/ml IL-1β, or a combination of both, over a 3-day period. Analysis of OA-related markers, such as MMP activity, the release of NO and GAGs, and the expression of PTGS2, allowed for the selection of the most effective inflammatory stimulus. Subsequently, explants challenged with TNFα+IL-1β were exposed to CM, consisting of a pool of concentrated supernatants from 72-h cultured ASCs, in order to evaluate its effect on cartilage catabolism and inflammation.
UNASSIGNED: The 3-day treatment with both 10ng/ml TNFα and 1ng/ml IL-1β significantly increased MMP activity and NO release, without affecting GAG release. The addition of CM significantly downregulated the abnormal MMP activity induced by the inflammatory stimuli, while also mildly reducing MMP3, MMP13, and PTGS2 gene expression. Finally, SOX9 and COL2A1 were downregulated by the cytokines, and further decreased by CM.
UNASSIGNED: The proposed cartilage explant model offers encouraging evidence of the therapeutic potential of ASC-derived CM against OA, and it could serve as a convenient ex vivo platform for drug screening.

The importance of mechanical loading and its relationship to orthobiologic therapies in the treatment of post-traumatic osteoarthritis (PTOA) is beginning to receive attention. This review explores the current efficacy of orthobiologic interventions, notably platelet-rich plasma (PRP), bone marrow aspirate (BMA), and mesenchymal stem/stromal cells (MSCs), in combating PTOA drawing from a comprehensive review of both preclinical animal models and human clinical studies. This review suggests why mechanical joint loading, such as running, might improve outcomes in PTOA management in conjunction with orthiobiologic administration. Accumulating evidence underscores the influence of mechanical loading on chondrocyte behavior and its pivotal role in PTOA pathogenesis. Dynamic loading has been identified as a key factor for optimal articular cartilage (AC) health and function, offering the potential to slow down or even reverse PTOA progression. We hypothesize that integrating the activation of mechanotransduction pathways with orthobiologic treatment strategies may hold a key to mitigating or even preventing PTOA development. Specific loading patterns incorporating exercise and physical activity for optimal joint health remain to be defined, particularly in the clinical setting following joint trauma.

UNASSIGNED: Hip osteoarthritis (OA) is one of the leading causes of disability and morbidity worldwide. It is estimated to affect 9.2% individuals globally with age over 45 years. Conventional treatment modalities have limitations and side-effects. To overcome these limitations, over the last decade, there has been an increased interest in the use of orthobiologics derived from autologous sources including platelet-rich plasma (PRP), bone-marrow aspirate concentrate (BMAC) and adipose tissue derived formulations. This review qualitatively presents the in-vitro, pre-clinical, clinical and on-going clinical studies exploring the safety and efficacy of BMAC for management of hip OA.
UNASSIGNED: The electronic database search was done through PubMed, Embase, Web of Science, Scopus, ProQuest and Google Scholar till February 2024. The search terms used were \"osteoarthritis\" OR \"hip osteoarthritis\" OR \"orthobiologics\" OR \"efficacy or use of orthobiologic treatment\" OR \"bone-marrow concentrate\" OR \"bone-marrow aspirate concentrate\", AND \"BMAC\". The inclusion criteria were clinical studies of any level of evidence written in the English language, published till February 2024, evaluating the safety and efficacy of intra-articular administration of BMAC for the management of hip OA.
UNASSIGNED: A total of 5 studies were included in this review for qualitative data synthesis. The total number of patients who participated in the study was 182, ranging from 4 to 112 in a single study. No adverse events were reported throughout the duration of the study. In addition, intra-articular administration of BMAC led to reduced pain, and improved function and overall quality of life (QoL).
UNASSIGNED: The results from this review demonstrated that administration of BMAC is safe and potentially efficacious in terms of reducing pain, improving function and overall QoL of patients with hip OA in short- and mid-term average follow-up based on the included studies. Nonetheless, more adequately powered, multi-center, prospective, double-blind, non-randomized and randomized controlled trials with long-term follow-up are warranted to establish long-term safety and efficacy of BMAC for management of hip OA and justify its routine clinical use.

UNASSIGNED: The knee is the most commonly affected joint in osteoarthritis (OA), affecting millions of people worldwide. Knee OA significantly impacts the activities of daily living (ADL) along with affecting overall quality of life of patients (QoL), thereby leading to substantial socio-economic burden. Conservative therapies are prioritized, resorting to surgery only when needed. However, these traditional approaches have limitations. Regenerative medicine, involving the use of orthobiologics, including autologous peripheral blood-derived orthobiologics such as growth factor concentrate (GFC), has evolved and shown potential for managing knee OA. The primary goal of this review is to summarize the results of in vitro, preclinical and clinical studies involving GFC for the management of knee OA.
UNASSIGNED: Multiple databases (PubMed, Scopus, Google Scholar, Web of Science and Embase) were searched applying terms for the intervention \'GFC\' and treatment \'knee OA\' for the studies published in the English language to March 10, 2024.
UNASSIGNED: Only three clinical studies met our pre-defined criteria and were included in this review.
UNASSIGNED: Intra-articular administration of GFC is safe and potentially efficacious to manage OA of the knee. More, adequately powered, multi-center, prospective, RCTs are warranted to demonstrate the long-term effectiveness of GFC in patients suffering from mild-to-moderate knee OA and to justify its routine clinical use. Further studies evaluating the efficacy of GFC compared to other orthobiologics are also required to allow physicians/surgeons to choose the optimal orthobiologic for the treatment of OA of the knee.